PROJECT SUMMARY: DOSIMETRY, PHYSICS & MODELING CORE We are proposing the creation of a research program entitled, ?Increasing the therapeutic index of brain tumor treatment through innovative FLASH radiotherapy (FLASH-RT), focused on translating a novel irradiation modality rapidly into the clinic. The overall hypothesis to be tested is whether radiation delivered at ultra high dose rates (compared to the much lower dose rates used in current clinical practice) can significantly ameliorate normal tissue complications while maintaining acceptable if not improved tumor control. To test this hypothesis, the program will deploy a comprehensive series of preclinical studies that will critically evaluate tumor control, neurocognitive outcomes and resultant radiation injury to the brain following FLASH-RT and conventional dose rate irradiation. Collectively, these studies will generate the requisite data sets required for the rapid translation of the novel FLASH irradiation platform to the clinical scenario. Preclinical studies in mice assessing orthotopic tumor control, cognition, neuronal and vascular structural plasticity, immune-modulation and oxygen dependent mechanisms of radiation injury are coupled with a clinical trial in GBM dog patients to inform the oncologists of the potential benefits of this potentially paradigm shifting technology. The objectives of this program project will be facilitated by the activities conducted by the Dosimetry, Physics & Modeling Core (Core 2) and the Neurobehavioral Core (Core 3). The Core 2 will develop three key innovations that will enable the rapid translation of FLASH-RT in to the clinic. First, we will develop and characterize dosimetric tools to accurately measure ultra-high dose rate beams. This will allow us to cross-validate the dosimetry between electron and photon FLASH radiation beams at each participating institution (Lausanne University Hospital, Stanford and Indiana Universities). Second, we will build and commission the first small animal conformal photon FLASH irradiation platform that will allow us to characterize the FLASH phenomenon with greater clinical relevance. Third, we will develop and implement the ?turn-key? technology for the conversion of a clinical medical linear accelerator to an experimental FLASH irradiator (Indiana University). The success of this innovative program project grant is bolstered by the unparalleled breadth and depth of our multi-disciplinary investigative team at UC Irvine, Stanford University, SLAC National Accelerator Laboratory, CHUV and Indiana University that has pioneered the development of the initial experimental infrastructure for conducting FLASH RT research and produced strong preclinical evidence of increased therapeutic index, comprising expertise in radiation oncology, radiobiology, medical physics, and preclinical imaging and accelerator science. In summary, Core 2 will develop the necessary dosimetric tools to support all projects, enable the cross validation of the dosimetry between all participating sites and between beam qualities, and thus ensuring experimental reproducibility between the irradiations systems at Lausanne University Hospital, Stanford and Indiana Universities.